Opioid Regulation Of Rat Hippocampal Neuronal Calcium Channels And Neural Synaptic Plasticity

Chronic exposure to opiates eventually leads to drug addiction. Opiates exert their effects through opioid receptors, Gi /o-coupled members of the heptahelical family of plasma membrane receptors. Studies on opiate addiction have been focused on some brain regions such as prefrontal cortex, nucleus accumbens, ventral tegmental area, and striatum, which are generally thought to be major components of the rewarding system. Hippocampus plays a key role in information encoding and retrieving in the central nervous system. It expresses opioid receptors widely, but the potential effects of chronic use of opiates on the function of hippocampus are poorly understood. Recent reports suggest that hippocampus is critical in the rewarding response and the relapse of drug seeking behavior. Using rat hippocampus as a model system, we investigated the effects of acute or chronic opiate treatment on the neuronal function and synaptic plasticity, and explored the underlying cellular and molecular mechanisms. (1) Nociceptin/orphanin FQ (N/OFQ), an endogenous ligand for opioid receptor-like receptor (ORL ), inhibites high-voltage gated calcium channel currents 1 via ORL . The N/OFQ inhibition of the calcium channel current was significantly 1 desensitized by pretreatment of freshly dissociated hippocampal neurons with the same peptide. Extracelluar calcium influx and protein kinase C were likely involved in the N/OFQ-induced desensitization. (2) Our results revealed that chronic exposure of rats to morphine or heroin markedly reduced the capacity of hippocampal CA1 LTP during the period of drug withdrawal. And the capacity of LTP could be restored to the normal level by re- exposure of the animals to opiates. Morris water maze test showed parallel learning deficits following chronic exposure to opiates. Moreover, the opiate-reduced LTP could also be restored by inhibitors of cAMP-dependent protein kinase A (PKA), suggesting that up-regulation of cAMP pathway was likely one of the underlying mechanisms of the observed phenomena. The above work demonstrates that opiates play an important role in modulating the function of hippocampus. Under physical conditions, voltage-dependent calcium channels (VGCCs) play a central role in controlling neurotransmitter release at the synapse, the modulation of VGCCs by N/OFQ may act as a .feedback. mechanism to finely regulate neurotransmitter release and synaptic plasticity in hippocampal neurons. After chronic opiate treatment, synaptic plasticity in the hippocampus was significantly modulated and became opiate dependent. These observations are of important significance for better understanding the molecular and neuronal mechanisms underlying drug addiction, especially the func...